Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema, inflammatory bowel diseases and parasitic infections ((see Bousquet, J. et al. N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan. C. J. Br. Med. Bull. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. It is established that chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4 activate eosinophils ((see Baggiolini, M. and Dahinden, C. A. Immunol. Today. 15:127-133 (1994), Rot, A. M. et al. J. Exp. Med. 176, 1489-1495 (1992) and Ponath. P. D. et al. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993) and Jose, P. J. et al. Biochem. Biophy. Res. Commun. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradermal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al. J. Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al. J. Exp. Med. 181, 1211 (1995) and Ponath. P. D. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)).
The CCR-3 receptor has been identified as a major chemokine receptor which eosinophils use for their response to eotaxin, RANTES and MCP-3. It is expressed predominantly on the surface of eosinophils and is highly selective for eotaxin. When transfected into a murine pre-β lymphoma line, the CCR-3 receptor bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to these chemokines ((see Ponath. P. D. et al. J. Exp. Med. 183, 2437-2448 (1996)).
Recently, studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 ((see Heath H. et al. J. Clin. Invest., Vol. 99, #2, 178-184 (1997)) indicating that CCR-3 antagonists are useful for the treatment of eosinophil-mediated inflammatory diseases.
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma ((R. P. Schleimer et. al., Am. Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients ((see Hanania N. A et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 (1995) and Saha M. T. et al, Acta Paediatrica, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects.
The present invention provides a means of combating eosinophil induced diseases, such as asthma.